Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress.

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Nature Cancer. 2022 Jun 02;3(7):866-884. doi: 10.1038/s43018-022-00389-8

Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress. Lippincott-Schwartz Lab

Liu X, Viswanadhapalli S, Kumar S, Lee T, Moore A, Ma S, Chen L, Hsieh M, Li M, Sareddy GR, Parra K, Blatt EB, Reese TC, Zhao Y, Chang A, Yan H, Xu Z, Pratap UP, Liu Z, Roggero CM, Tan Z, Weintraub ST, Peng Y, Tekmal RR, Arteaga CL, Lippincott-Schwartz J, Vadlamudi RK, Ahn J, Raj GV

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Abstract

Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. Herein we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds LIPA. ERX-41 induces endoplasmic reticulum (ER) stress resulting in cell death, and this effect is on target as evidenced by specific LIPA mutations providing resistance. Importantly, we demonstrate that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. This targeted vulnerability has a large therapeutic window, with no adverse effects either on normal mammary epithelial cells or in mice. Our study implicates a targeted strategy for solid tumors, including breast, brain, pancreatic and ovarian, whereby small, orally bioavailable molecules targeting LIPA block protein folding, induce ER stress and result in tumor cell death.

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Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress.

Abstract

PMID: 35654861 [PubMed - indexed for MEDLINE]

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